No / The pro-opiomelanocortin (POMC)-derived peptides, -melanocyte-stimulating hormone, and adrenocorticotropic hormone, are important mediators of human skin pigmentation via action at the melanocortin-1 receptor. Recent data suggests that such a regulatory role also exists for the endogenous opiate, -endorphin (-END). A role for this -END in the regulation of follicular pigmentation, however, has not been determined. This study was designed to examine the involvement of the -END/-opiate receptor system in human follicular melanocyte biology. We employed RT-PCR, and immunohisto/cytochemistry and immunoelectron microscopy using -END and -opiate receptor specific antibodies and a functional role for -END was assessed by direct stimulation with the peptide. This study has demonstrated that human hair follicle melanocytes (HFM) express mRNA for the -opiate receptor and POMC. Furthermore, -END and its high affinity -opiate receptor are expressed at the protein level in glycoprotein100-positive follicular melanocytes and as a function of their anatomic location and differentiation status during the hair growth cycle. Functional studies revealed that -END is a modifier of HFM phenotype via its ability to upregulate melanogenesis, dendricity, and proliferation. These findings suggest a new regulatory role for -END in human HFM biology, providing a new research direction into the fundamental regulation of human hair pigmentation.